Atherosclerosis is the leading cause of mortality in the western world. HDL, the levels of which are inversely[unreadable] correlated with the risk of atherosclerosis, exerts its protective effect in large part through its ability to[unreadable] mobilize cholesterol from peripheral cells and to stimulate reverse cholesterol transport to the liver.[unreadable] Atherosclerosis and inflammation share many common features and the atherosclerotic process exhibits[unreadable] characteristics of chronic inflammation. Inflammation significantly alters HDL structure, composition and[unreadable] levels, but the underlying mechanisms and the consequences of such modifications are not understood. In[unreadable] studying the impact of HDL on atherosclerosis it is therefore critical to understand how such HDL[unreadable] modifications, that can result both systemically and within the microenvironment of the atherosclerotic lesion,[unreadable] influence HDL metabolism and its role in cholesterol transport. Inflammatory modifications in HDL may also[unreadable] alter the protective effect of HDL in neutralizing the inflammatory effects of bacterial lipopolysaccharides.[unreadable] Inflammation and the acute-phase response results in a marked induction of acute phase proteins including[unreadable] serum amyloid A (SAA), which becomes a major HDL apolipoprotein. Recently, we identified two Class B[unreadable] scavenger receptors, SR-BI and CD36, as high-affinity receptors for SAA and also showed that SAA[unreadable] promotes cellular cholesterol efflux. Further, SR-BI and CD36 were shown to efficiently take up SAA into[unreadable] cells, a process that may be important in the function and metabolism of SAA. In this proposal we will[unreadable] examine the overall hypothesis that HDL cholesterol transport by Class B scavenger receptors is significantly[unreadable] altered during inflammation through the effects of acute phase proteins and modifications in HDL structure.[unreadable] Aim 1 will examine the hypothesis that the Class B scavenger receptors mediate the cellular uptake and[unreadable] catabolism of SAA. Studies will investigate the roles of SR-BI and CD36 in the cellular uptake, recycling and[unreadable] degradation of SAA in hepatocytes and macrophages. Aim 2 will determine how SAA and HDL remodeling[unreadable] during inflammation impacts HDL cholesterol transport by Class B scavenger receptors. Studies will[unreadable] investigate how SAA and acute phase modifications of HDL influence SR-BI-dependent cholesterol efflux[unreadable] from hepatocytes and macrophages and SR-BI-mediated selective lipid uptake into hepatocytes. Aim 3 will[unreadable] test the hypothesis that Class B scavenger receptors and SAA regulate the LPS-induced inflammatory[unreadable] response. Studies will examine the roles of SR-BI and CD36 in LPS- and LTA-induced inflammation and the[unreadable] modulating effects of SAA. These studies are expected to provide greater understanding of how[unreadable] inflammation influences the protective function of HDL.